Project Summary/Abstract In the United States, hepatocellular carcinoma has one of the most rapidly increasing incidence rates among both men and women. This sharp increase in incidence is coupled with a median survival of less than one year, as most liver cancer cases are diagnosed at late stages and are not eligible for curative therapy, while outcomes dramatically improve for asymptomatic, early stage localized hepatocellular carcinoma, with significant improved 5-year survival rates with surgical resection or liver transplantation. Furthermore, there is currently no effective surveillance strategy for early hepatocellular carcinoma detection in clinical practice. We therefore propose to identify new hepatocellular carcinoma-specific plasma protein biomarkers that can contribute to the detection of early stage hepatocellular carcinoma when cure is more likely. Although proteomics is an extremely useful and high-throughput analytical platform for hepatocellular carcinoma biomarker discovery, identifying biomarkers through proteomics-based approaches is limited due to the lack of a systematic proteome screen and its limited ability to accurately detect low-abundance proteins. SOMAscan, a novel highly multiplexed, high sensitivity aptamer-based immuno-like biomarker discovery technology, has been applied successfully for biomarker discovery in some other diseases. More recently, based on our preliminary data, we provide solid evidence as to the potential ability of SOMAscan to identify novel, low abundance, blood-based biomarkers in liver diseases with great accuracy. We will therefore apply SOMAscan to hepatocellular carcinoma by systematically measuring the expression level of 1,305 biologically relevant human plasma proteins, including low abundant cytokines across the whole dynamic range. We will further validate the candidate protein biomarkers in an independent study using ELISA. Upon completion of this proposed study we expect to have identified novel plasma protein biomarkers that could contribute to early detection of hepatocellular carcinoma and generate new insights into hepatocellular carcinoma pathogenesis. The integration of proteomics within the cohorts and the state-of-the-art proteomics platform has the potential to ultimately transform hepatocellular carcinoma detection and management, therefore reducing the mortality of this deadly disease.